The NMDA receptor antagonist eliprodil (SL 82.0715) blocks voltage-operated Ca2+ channels in rat cultured cortical neurons

doi:10.1016/0014-2999(94)90142-2

European Journal of Pharmacology

Volume 257, Issue 3, 23 May 1994, Pages 297-301

https://doi.org/10.1016/0014-2999(94)90142-2 Get rights and content

Abstract

The effect of the non-competitive NMDA receptor antagonist eliprodil on NMDA receptor- and voltage-operated Ca²⁺ currents was investigated in rat cultured cortical neurons by using the whole-cell patch clamp technique. With neurons voltage-clamped at −40 mV, eliprodil reduced in concentration-dependent manner the inward current induced by $N- methyl- D -aspartate$ (NMDA) (10 μM) in the presence of D-serine with an IC₅₀ of 0.67 μM (I_max=83%). Eliprodil also blocked the total inward Ba²⁺ current carried in part by L- and N-type Ca²⁺ channels with an IC₅₀ of 1.48 μM (I_max=87%). These results suggest that the neuroprotective properties of eliprodil could be due to its combined ability to antagonize the NMDA receptor- and voltage-operated Ca²⁺ channels.

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Cited by (35)

Synthesis and biological evaluation of conformationally restricted GluN2B ligands derived from eliprodil
2022, European Journal of Medicinal Chemistry
Citation Excerpt :
Eliprodil (2) is a less potent GluN2B NMDA receptor antagonist than ifenprodil [23], but has equally strong neuroprotective properties in animal models of cerebral ischemia [24]. Since eliprodil (2) inhibits voltage dependent Ca2+ channels, its neuroprotective properties may be due to the action as dual antagonist [25]. The synthesis of tropane analogs of type 6 started with Boc-protected tropanone 7 [26].
N-Methyl-d-aspartate (NMDA) receptors containing one or two GluN2B subunits play a crucial role in a variety of neurodegenerative diseases, such as Alzheimer's and Huntington's disease. In order to increase selectivity for GluN2B NMDA receptors, the piperidine ring of eliprodil (2) was conformationally restricted by introduction of an ethano bridge across C-2 and C-6 resulting in a tropane scaffold. Benzylidenetropanes 15 and 16 and benzyltropanes 17 and 18 were prepared by nucleophilic opening of enantiomerically pure phenyloxiranes 13 and 14 with racemic secondary amines (Z/E)-11 and diastereomeric mixtures (r/s)-12. The diastereomers were separated by preparative HPLC to obtain enantiomerically pure test compounds 15–18. The absolute and relative configuration of the products were determined by X-ray crystal structure analysis. Benzylidenetropanes 15 and 16 as well as benzyltropanes 17 and 18 display very high GluN2B affinity in receptor binding studies. Benzylidinetropanes with the phenyl moiety oriented towards C-5 of the tropane system showed higher GluN2B affinity than their analogs with the phenyl moiety oriented towards C-1. In benzyltropanes endo-configured stereoisomers exhibit higher GluN2B affinity than exo-configured diastereomers. Unfortunately, tropanes 15–18 show also high σ₁ and σ₂ affinity with the same trends for the stereoisomers as for GluN2B affinity. The high-affinity GluN2B ligand (R,r)-17b was able to inhibit the ion flux in two-electrode voltage clamp experiments using GluN1a/GluN2B expressing oocytes.
Retinal ischemia: Mechanisms of damage and potential therapeutic strategies
2004, Progress in Retinal and Eye Research
Retinal ischemia is a common cause of visual impairment and blindness. At the cellular level, ischemic retinal injury consists of a self-reinforcing destructive cascade involving neuronal depolarisation, calcium influx and oxidative stress initiated by energy failure and increased glutamatergic stimulation. There is a cell-specific sensitivity to ischemic injury which may reflect variability in the balance of excitatory and inhibitory neurotransmitter receptors on a given cell. A number of animal models and analytical techniques have been used to study retinal ischemia, and an increasing number of treatments have been shown to interrupt the “ischemic cascade” and attenuate the detrimental effects of retinal ischemia.
Thus far, however, success in the laboratory has not been translated to the clinic. Difficulties with the route of administration, dosage, and adverse effects may render certain experimental treatments clinically unusable. Furthermore, neuroprotection-based treatment strategies for stroke have so far been disappointing. However, compared to the brain, the retina exhibits a remarkable natural resistance to ischemic injury, which may reflect its peculiar metabolism and unique environment. Given the increasing understanding of the events involved in ischemic neuronal injury it is hoped that clinically effective treatments for retinal ischemia will soon be available.
Interactions of intrathecally administered ziconotide, a selective blocker of neuronal N-type voltage-sensitive calcium channels, with morphine on nociception in rats
2000, Pain
Citation Excerpt :
In contrast, it has been shown that NMDA receptor antagonists such as MK-801 block morphine tolerance to analgesia (Trujillo and Akil, 1991; Gutstein and Trujillo, 1993) in the spinal cord (Gutstein and Trujillo, 1993). NMDA receptors antagonists are known to block voltage-dependent calcium currents including N-type currents (Church et al., 1994; Biton et al., 1994). Our results with ziconotide suggest that inhibition of spinal N-type calcium channels is not involved in the effect of NMDA receptor antagonists on morphine tolerance.
Ziconotide is a selective, potent and reversible blocker of neuronal N-type voltage-sensitive calcium channels (VSCCs). Morphine is an agonist of μ-opioid receptors and inhibits N-type VSCC channels via a G-protein coupling mechanism. Both agents are antinociceptive when they are administered intrathecally (spinally). The present study investigated the acute and chronic (7-day) interactions of intrathecally administered ziconotide and morphine on nociception in several animal models of pain. In the acute study, intrathecal bolus injections of morphine and ziconotide alone produced dose-dependent inhibition of formalin-induced tonic flinch responses and withdrawal responses to paw pressure. The combination of ziconotide and morphine produced an additive inhibition of formalin-induced tonic flinch responses and a significant leftward shift of the morphine dose-response curve in the paw pressure test. After chronic (7-day) intrathecal infusion, ziconotide enhanced morphine analgesia in the formalin test. In contrast, chronic intrathecal morphine infusion produced tolerance to analgesia, but did not affect ziconotide antinociception. Antinociception produced by ziconotide alone was the same as that observed when the compound was co-administered with morphine to morphine-tolerant rats. In the hot-plate and tail immersion tests, chronic intrathecal infusion of morphine lead to rapid tolerance whereas ziconotide produced sustained analgesia with no loss of potency throughout the infusion period. Although ziconotide in combination with morphine produced an apparent synergistic analgesic effects during the initial phase of continuous infusion, it did not prevent morphine tolerance to analgesia. These results demonstrate that (1) acute intrathecal administrations of ziconotide and morphine produce additive or synergistic analgesic effects; (2) chronic intrathecal morphine infusion results in tolerance to analgesia but does not produce cross-tolerance to ziconotide; (3) chronic intrathecal ziconotide administration produces neither tolerance nor cross-tolerance to morphine analgesia; (4) intrathecal ziconotide does not prevent or reverse morphine tolerance.
Anticonvulsant effects of eliprodil alone or combined with the glycine(B) receptor antagonist L-701,324 or the competitive NMDA antagonist CGP 40116 in the amygdala kindling model in rats
1999, Neuropharmacology
The discovery that glutamate’s activity at the N-methyl-d-aspartate (NMDA) receptor is positively modulated by glycine and polyamines has led to a new pharmacological strategy that NMDA receptor-mediated events could be antagonized indirectly at the strychnine-insensitive glycine co-agonist site (glycine_B receptor) and the polyamine modulatory site. Recently we demonstrated that ifenprodil and L-701,324 (7-chloro-4-hydroxy-3(3-phenoxy)phenyl-2(H)quinoline), polyamine and glycine_B receptor antagonists, respectively, at subeffective doses markedly increased after-discharge threshold (ADT) when applied together in amygdala-kindled rats. Because ifenprodil and its derivative, eliprodil, exhibit different affinities for NMDA receptors composed of different subunits, our current question was whether a combination of eliprodil and the glycine_B receptor antagonist, L-701,324, would produce a super-additive anticonvulsant action. In addition, we examined the combined treatment of eliprodil with a competitive NMDA receptor antagonist CGP 40116 (d-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid) in the kindling model. Eliprodil alone (10–40 mg/kg) had no consistent ADT-increasing activity. When eliprodil was combined with an ineffective dose of L-701,324 (2.5 mg/kg), a significant rise in ADT was observed. Likewise, other measures of seizure activity such as severity and duration were modestly but significantly reduced. With respect to behavioral impairments, no signs of synergistic interaction were observed after the drug combinations. On the other hand, no anticonvulsant effects were found when CGP 40116 was administered alone at doses of 1.25–5 mg/kg or CGP 40116 1.25 mg/kg combined with eliprodil 10 mg/kg. These data suggest that combination therapy with antagonists at the polyamine and glycine sites might potentially treat therapy-resistant complex partial seizures.
Eliprodil, a non-competitive, NR2B-selective NMDA antagonist, protects pyramidal neurons in hippocampal slices from hypoxic/ischemic damage
1998, Brain Research
The N-methyl-d-aspartate (NMDA) subtype of glutamate receptor is one pathway through which excessive influx of calcium has been suggested to trigger ischemia-induced delayed neuronal death. NMDA receptors are heterooligomeric complexes comprised of both NR1 and NR2A-D subunits, in various combinations. NR2B-containing NMDA complexes exhibit larger, more prolonged conductances than those lacking this subunit. We tested the ability of the non-competitive, NR2B-selective NMDA antagonist eliprodil to (a) protect synaptic transmission in in vitro hippocampal slices from hypoxia, and (b) reduce ischemic delayed neuronal death in hippocampal organotypic slice cultures. Eliprodil markedly improved the recovery of Schaffer collateral-CA1 excitatory postsynaptic potentials following a 15 min hypoxic insult, with an EC50 of approximately 0.5 μM. In contrast to this functional protection, eliprodil did not reduce delayed death of CA1 pyramidal neurons in organotypic hippocampal slice cultures treated with severe hypoxia plus hypoglycemia, though it did potently protect CA3 pyramidal neurons in the same cultures. These data indicate that NMDA receptors containing NR2B subunits may play a role in long-term recovery of hippocampal synaptic function following ischemia/hypoxia. Furthermore, the selective protection of CA3, but not CA1, pyramidal neurons suggests that NR2B-containing NMDA receptors may preferentially contribute to an excitotoxic component of ischemia-induced delayed neuronal death.
The pharmacology of native N-methyl-D-aspartate receptor subtypes: Different receptors control the release of different striatal and spinal transmitters
1998, Progress in Neuro-Psychopharmacology and Biological Psychiatry
- 1.
  1. N-methyl-D-aspartate (NMDA) increases the release of radiolabelled dopamine, GABA, acetylcholine and spermidine from rat striatal slices and of noradrenaline from the dorsal cervical spinal cord.
- 2.
  2. These five responses show differing sensitivities to NMDA and also to a variety of competitive antagonists, NMDA channel blockers, glycine antagonists and polyamine site antagonists.
- 3.
  3. Inhibitory activity profiles for 20 different antagonists are presented. All compounds tested showed some degree of selectivity with regard to the different responses and each response showed particular characteristics that suggested mediation by a particular native NMDA receptor subtype.
- 4.
  4 Receptors controlling dopamine, GABA and noradrenaline release were generally more sensitive to most antagonists compared to those controlling acetylcholine and spermidine release.
- 5.
  5. Receptors controlling spermidine release were furthermore insensitive to magnesium, argiotoxin, ifenprodil and eliprodil and displayed low sensitivity to memantine, dextrorphan and dextromethorphan.
- 6.
  6. Receptors controlling noradrenaline release could be further discriminated from those controlling dopamine and GABA release by very high sensitivity to magnesium and MK-801 and to the glycine antagonist L-689,560 but not to other glycine antagonists (CNQX, DNQX, 7-Chlorokynurenate, HA-966).
- 7.
  7. Many other individual drug or receptor differences were noted. The different profiles observed suggest a wide diversity of native NMDA receptors with different properties and an unexpectedly rich pharmacopeia of subtype selective antagonists of native NMDA receptors.
- 8.
  8. Matching subtype selectivity to particular behavioural effects may be possible and the design of subtype selective NMDA antagonists for particular clinical applications while avoiding side effect generation seems to be feasible.

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Short communicationThe NMDA receptor antagonist eliprodil (SL 82.0715) blocks voltage-operated Ca2+ channels in rat cultured cortical neurons

Abstract

Trends Neurosci.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Trends Neurosci.

Brain Res.

Neuroscience

Short communication
The NMDA receptor antagonist eliprodil (SL 82.0715) blocks voltage-operated Ca²⁺ channels in rat cultured cortical neurons